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Transcriptional Regulation By The Oncogenic Znf217/Corest Complex, Gobi Thillainadesan

Electronic Thesis and Dissertation Repository

The ZNF217 transcription factor is an oncogene found within the 20q13 amplicon and is amplified and overexpressed in many cancers including breast and ovarian. Overexpression of ZNF217 leads to increased cell proliferation, survival, and causes resistance to TGFβ's anti-proliferative effects.

ZNF217 is a core constituent of a transcriptional complex that includes CoREST, HDAC1/2, LSD1, and the CtBP1/2. In this study, I have combined genome-wide biochemical approaches to identify genes directly regulated by ZNF217. I have identified the tumor suppressor and cell cycle inhibitor, p15^ink4b, as a direct target of the ZNF217 complex and demonstrated that ZNF217 represses the …

Characterizing The Contribution Of The Lxcxe Binding Cleft To Prb-Mediated Genome Stability And Tumor Suppression, Courtney H. Coschi

Electronic Thesis and Dissertation Repository

Condensation and segregation of mitotic chromosomes are critical processes for cellular propagation and if compromised, can lead to genomic instability. Genomic instability is known to be an active contributor to tumorigenesis, rather than being a by-product of malignant progression. The retinoblastoma protein (pRB) is the prototypic tumor suppressor. Its tumor suppressive properties are linked to its ability to negatively regulate proliferation by inhibiting E2F target gene transcription. Using a gene targeted mouse model defective for interactions mediated by the pRB LXCXE binding cleft that is distinct from E2F binding (Rb1^ΔL/ΔL), I have demonstrated that LXCXE-interactions are an …

Interpretation, Stratification And Validation Of Sequence Variants Affecting Mrna Splicing In Complete Human Genome Sequences, Ben C. Shirley

Electronic Thesis and Dissertation Repository

The Shannon Human Splicing Pipeline software has been developed to analyze variants on a genome-scale. Evidence is provided that this software predicts variants affecting mRNA splicing. Variants are examined through information-based analysis and the context of novel mutations as well as common and rare SNPs with splicing effects are displayed. Potential natural and cryptic mRNA splicing variants are identified, and inactivating mutations are distinguished from leaky mutations. Mutations and rare SNPs were predicted in genomes of three cancer cell lines (U2OS, U251 and A431), supported by expression analyses. After filtering, tractable numbers of potentially deleterious variants are predicted by the …